Antibodies cross-reacting with thyroglobulin and thyroid peroxidase are induced by immunization of rabbits with an immunogenic thyroglobulin 20mer peptide

Thrasyvoulides, Apollon; Lymberi, Peggy

doi:10.1111/j.1365-2249.2004.02657.x

Cited by 11 publications

(4 citation statements)

References 33 publications

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“…Induced and spontaneous intermolecular spreading for thyroid autoantibodies has been demonstrated for thyroid autoimmunity (Table 2 ). For example, rabbits immunized with human Tg and complete Freund’s adjuvant develop antibodies to Tg, as expected, as well as antibodies to TPO and antibodies that bind to both Tg and TPO ( 85 , 86 ). It should be noted that searching for previously postulated bispecific human autoantibodies that recognize both Tg and TPO (“TgPO antibodies”) [for example, Ref.…”

Section: Epitope Spreading Of Thyroid Autoantibodiessupporting

confidence: 53%

Thyroid Autoantibodies Display both “Original Antigenic Sin” and Epitope Spreading

McLachlan

Rapoport

2017

Front. Immunol.

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Evidence for original antigenic sin in spontaneous thyroid autoimmunity is revealed by autoantibody interactions with immunodominant regions on thyroid autoantigens, thyroglobulin (Tg), thyroid peroxidase (TPO), and the thyrotropin receptor (TSHR) A-subunit. In contrast, antibodies induced by immunization of rabbits or mice recognize diverse epitopes. Recognition of immunodominant regions persists despite fluctuations in autoantibody levels following treatment or over time. The enhancement of spontaneously arising pathogenic TSHR antibodies in transgenic human thyrotropin receptor/NOD.H2h4 mice by injecting a non-pathogenic form of TSHR A-subunit protein also provides evidence for original antigenic sin. From other studies, antigen presentation by B cells, not dendritic cells, is likely responsible for original antigenic sin. Recognition of restricted epitopes on the large glycosylated thyroid autoantigens (60-kDa A-subunit, 100-kDa TPO, and 600-kDa Tg) facilitates exploring the amino acid locations in the immunodominant regions. Epitope spreading has also been revealed by autoantibodies in thyroid autoimmunity. In humans, and in mice that spontaneously develop autoimmunity to all three thyroid autoantigens, autoantibodies develop first to Tg and later to TPO and the TSHR A-subunit. The pattern of intermolecular epitope spreading is related in part to the thyroidal content of Tg, TPO and TSHR A-subunit and to the molecular sizes of these proteins. Importantly, the epitope spreading pattern provides a rationale for future antigen-specific manipulation to block the development of all thyroid autoantibodies by inducing tolerance to Tg, first in the autoantigen cascade. Because of its abundance, Tg may be the autoantigen of choice to explore antigen-specific treatment, preventing the development of pathogenic TSHR antibodies.

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Section: Epitope Spreading Of Thyroid Autoantibodiessupporting

confidence: 53%

Thyroid Autoantibodies Display both “Original Antigenic Sin” and Epitope Spreading

McLachlan

Rapoport

2017

Front. Immunol.

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“…The reason for this epitope masking is currently not clear, but it is intriguing to speculate that this phenomenon might reduce the potential immunogenicity of some of the therapeutic Abs when comprised in a pAb composition. Also, these studies demonstrated the absence of epitope spreading (18,19). Hence, Abs which are nonimmunogenic when administered individually did not become immunogenic as part of a pAb composition.…”

Section: Discussionmentioning

confidence: 92%

Reduced Susceptibility of Recombinant Polyclonal Antibodies to Inhibitory Anti-Variable Domain Antibody Responses

Klitgaard

Coljee

Andersen

et al. 2006

The Journal of Immunology

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The immunogenicity of therapeutic Abs is a concern as anti-drug Abs may impact negatively on the pharmacodynamics and safety profile of Ab drugs. The factors governing induction of anti-drug Abs are not fully understood. In this study, we describe a model based on mouse-human chimeric Abs for the study of Ab immunogenicity in vivo. Six chimeric Abs containing human V regions and mouse C regions were generated from six human anti-Rhesus D Abs and the Ag-binding characteristics of the parental human Abs were retained. Analysis of the immune response toward the individual chimeric Abs revealed the induction of anti-variable domain Abs including anti-idiotypic Abs against some of these, thereby demonstrating the applicability of the model for studying anti-drug Ab responses in vivo. Immunization of BALB/c, C57, and outbred NMRI mice with a polyclonal composition consisting of all six chimeric Abs demonstrated that the immunogenicity of the individual Abs was haplotype dependent. Chimeric Abs, which were nonimmunogenic when administered individually, did not become immunogenic as part of the polyclonal composition, implying the absence of epitope spreading. Ex vivo Ab-binding studies established a clear correlation between the level of immunogenicity of the Abs comprised in the composition and the impact on the pharmacology of the Abs. These analyses demonstrate that under these conditions this polyclonal Ab composition was generally less susceptible to blocking Abs than the respective mAbs.

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“…Recently, we identified spreading of B cell epitopes within the molecule of Tg (intramolecular spreading) after active immunization with a 20mer Tg peptide [5]. This intramolecular spreading in Tg resulted in intermolecular spreading of antibody reactivity to another thyroid antigen, thyroid peroxidase (TPO) [6].…”

Section: Introductionmentioning

confidence: 99%

“…Immunization of rabbits with Tg is known to result in the generation of antibodies to the thyroid antigen TPO [6]. In the present study we investigated spreading of antibody reactivity to non‐thyroid autoantigens during immunization of rabbits with human Tg.…”

Section: Introductionmentioning

confidence: 99%

Spreading of antibody reactivity to non-thyroid antigens during experimental immunization with human thyroglobulin

Thrasyvoulides¹,

Liakata

Lymberi

2006

Clinical and Experimental Immunology

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SummaryIntermolecular spreading of antibody reactivity has been implicated in the evolution of autoimmune disease. In this study, spreading of antibody reactivity to non-thyroid autoantigens after experimental immunization with thyroglobulin (Tg) was investigated. For this purpose, two rabbits were injected with human Tg six times (stages 1-6) every 3 weeks. Animals were also bled before priming. Antisera were tested by enzyme-linked immunosorbent assay (ELISA) for reactivity to several non-thyroid antigens: bovine serum albumin (BSA), native DNA (nDNA), human myosin, human globular (G) and filamentous (F) actin and porcine tubulin. Tg-immunized animals developed the following serological reactivity pattern: (a) high reactivity to myosin from stage 2 onward, (b) significant reactivity to F-actin, remaining high up to stage 6, (c) reactivity to BSA with a peak at stage 3, (d) a small increase of reactivity to G-actin at stage 3 and (e) no increase of reactivity to nDNA and tubulin. The study of affinity-purified anti-Tg antibodies and the use of competitive assays revealed that reactivity to F-actin was not due to cross-reaction with Tg. On the contrary, reactivity to myosin during the first stages of immunization was due to cross-reaction with Tg, while at stage 6 it became myosin-specific. Reactivity to BSA at stage 3 was also due to cross-reaction with Tg. We conclude that at least part of the induced anti-Tg antibodies may result from the expansion of B cell clones producing polyreactive natural autoantibodies, and polyreactivity of anti-Tg antibodies during the first stages of Tg-immunization may be responsible for the intermolecular spreading of antibody response.

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Antibodies cross-reacting with thyroglobulin and thyroid peroxidase are induced by immunization of rabbits with an immunogenic thyroglobulin 20mer peptide

Cited by 11 publications

References 33 publications

Thyroid Autoantibodies Display both “Original Antigenic Sin” and Epitope Spreading

Thyroid Autoantibodies Display both “Original Antigenic Sin” and Epitope Spreading

Reduced Susceptibility of Recombinant Polyclonal Antibodies to Inhibitory Anti-Variable Domain Antibody Responses

Spreading of antibody reactivity to non-thyroid antigens during experimental immunization with human thyroglobulin

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